HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------------ WARNINGS and PRECAUTIONS ------------------------

HIGHLIGHTS OF PRESCRIBING INFORMATION ------------------------ WARNINGS and PRECAUTIONS ------------------------

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use COREG
safely and effectively. See full prescribing information for COREG.
------------------------ WARNINGS and PRECAUTIONS -----------------------•
Acute exacerbation of coronary artery disease upon cessation of therapy:
Do not abruptly discontinue. (5.1)
•
Bradycardia, hypotension, worsening heart failure/fluid retention may
occur. Reduce the dose as needed. (5.2, 5.3, 5.4)
•
Non-allergic bronchospasm (e.g., chronic bronchitis and emphysema):
Avoid β-blockers. (4) However, if deemed necessary, use with caution
and at lowest effective dose. (5.5)
•
Diabetes: Monitor glucose as β-blockers may mask symptoms of
hypoglycemia or worsen hyperglycemia. (5.6)
COREG (carvedilol) tablets
Initial U.S. Approval: 1995
----------------------------INDICATIONS AND USAGE ---------------------------COREG is an alpha/beta-adrenergic blocking agent indicated for the treatment
of:
•
Mild to severe chronic heart failure (1.1)
•
Left ventricular dysfunction following myocardial infarction in clinically
stable patients (1.2)
•
Hypertension (1.3)
------------------------------ ADVERSE REACTIONS -----------------------------Most common adverse events (6.1):
•
Heart failure and left ventricular dysfunction following myocardial
infarction (≥10%): Dizziness, fatigue, hypotension, diarrhea,
hyperglycemia, asthenia, bradycardia, weight increase
•
Hypertension (≥5%): Dizziness
To report SUSPECTED ADVERSE REACTIONS, contact
GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
----------------------- DOSAGE AND ADMINISTRATION ----------------------Take with food. Individualize dosage and monitor during up-titration. (2)
•
Heart failure: Start at 3.125 mg twice daily and increase to 6.25, 12.5,
and then 25 mg twice daily over intervals of at least 2 weeks. Maintain
lower doses if higher doses are not tolerated. (2.1)
•
Left ventricular dysfunction following myocardial infarction: Start at
6.25 mg twice daily and increase to 12.5 mg then 25 mg twice daily after
intervals of 3 to 10 days. A lower starting dose or slower titration may
be used. (2.2)
•
Hypertension: Start at 6.25 mg twice daily and increase if needed for
blood pressure control to 12.5 mg then 25 mg twice daily over intervals
of 1 to 2 weeks. (2.3)
------------------------------- DRUG INTERACTIONS ------------------------------•
CYP P450 2D6 enzyme inhibitors may increase and rifampin may
decrease carvedilol levels. (7.1, 7.5)
•
Hypotensive agents (e.g., reserpine, MAO inhibitors, clonidine) may
increase the risk of hypotension and/or severe bradycardia. (7.2)
•
Cyclosporine or digoxin levels may increase. (7.3, 7.4)
•
Both digitalis glycosides and β-blockers slow atrioventricular
conduction and decrease heart rate. Concomitant use can increase the
risk of bradycardia. (7.4)
•
Amiodarone may increase carvedilol levels resulting in further slowing
of the heart rate or cardiac conduction. (7.6)
•
Verapamil- or diltiazem-type calcium channel blockers may affect ECG
and/or blood pressure. (7.7)
•
Insulin and oral hypoglycemics action may be enhanced. (7.8)
--------------------- DOSAGE FORMS AND STRENGTHS --------------------Tablets: 3.125 mg, 6.25 mg, 12.5 mg, 25 mg (3)
-------------------------------CONTRAINDICATIONS ------------------------------•
Bronchial asthma or related bronchospastic conditions. (4)
•
Second- or third-degree AV block. (4)
•
Sick sinus syndrome. (4)
•
Severe bradycardia (unless permanent pacemaker in place). (4)
•
Patients in cardiogenic shock or decompensated heart failure requiring the
use of IV inotropic therapy. (4)
•
Severe hepatic impairment. (2.4, 4)
•
History of serious hypersensitivity reaction (e.g., Stevens-Johnson
syndrome, anaphylactic reaction, angioedema) to any component of this
medication or other medications containing carvedilol. (4)
See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling.
Revised: 08/2013
7.2 Hypotensive Agents 7.3 Cyclosporine 7.4 Digitalis Glycosides 7.5 Inducers/Inhibitors of Hepatic Metabolism 7.6 Amiodarone 7.7 Calcium Channel Blockers 7.8 Insulin or Oral Hypoglycemics 7.9 Anesthesia 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Specific Populations 12.5 Drug-Drug Interactions 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility 14 CLINICAL STUDIES 14.1 Heart Failure 14.2 Left Ventricular Dysfunction Following
Myocardial Infarction 14.3 Hypertension 14.4 Hypertension With Type 2 Diabetes Mellitus 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION 17.1 Patient Advice *Sections or subsections omitted from the full prescribing information are not
listed.
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE 1.1 Heart Failure 1.2 Left Ventricular Dysfunction Following
Myocardial Infarction 1.3 Hypertension 2 DOSAGE AND ADMINISTRATION 2.1 Heart Failure 2.2 Left Ventricular Dysfunction Following
Myocardial Infarction 2.3 Hypertension 2.4 Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cessation of Therapy 5.2 Bradycardia 5.3 Hypotension 5.4 Heart Failure/Fluid Retention 5.5 Non-allergic Bronchospasm 5.6 Glycemic Control in Type 2 Diabetes 5.7 Peripheral Vascular Disease 5.8 Deterioration of Renal Function 5.9 Major Surgery 5.10 Thyrotoxicosis 5.11 Pheochromocytoma 5.12 Prinzmetal’s Variant Angina 5.13 Risk of Anaphylactic Reaction 5.14 Intraoperative Floppy Iris Syndrome 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Laboratory Abnormalities 6.3 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 CYP2D6 Inhibitors and Poor Metabolizers 1
______________________________________________________________________
FULL PRESCRIBING INFORMATION
1
1.1
INDICATIONS AND USAGE
Heart Failure
COREG® is indicated for the treatment of mild-to-severe chronic heart failure of
ischemic or cardiomyopathic origin, usually in addition to diuretics, ACE inhibitors, and
digitalis, to increase survival and, also, to reduce the risk of hospitalization [see Drug
Interactions (7.4) and Clinical Studies (14.1)].
1.2
Left Ventricular Dysfunction Following Myocardial Infarction
COREG is indicated to reduce cardiovascular mortality in clinically stable patients who
have survived the acute phase of a myocardial infarction and have a left ventricular ejection
fraction of ≤40% (with or without symptomatic heart failure) [see Clinical Studies (14.2)].
1.3
Hypertension
COREG is indicated for the management of essential hypertension [see Clinical Studies
(14.3, 14.4)]. It can be used alone or in combination with other antihypertensive agents,
especially thiazide-type diuretics [see Drug Interactions (7.2)].
2
DOSAGE AND ADMINISTRATION
COREG should be taken with food to slow the rate of absorption and reduce the
incidence of orthostatic effects.
2.1
Heart Failure
DOSAGE MUST BE INDIVIDUALIZED AND CLOSELY MONITORED BY A
PHYSICIAN DURING UP-TITRATION. Prior to initiation of COREG, it is recommended that
fluid retention be minimized. The recommended starting dose of COREG is 3.125 mg twice
daily for 2 weeks. If tolerated, patients may have their dose increased to 6.25, 12.5, and 25 mg
twice daily over successive intervals of at least 2 weeks. Patients should be maintained on lower
doses if higher doses are not tolerated. A maximum dose of 50 mg twice daily has been
administered to patients with mild-to-moderate heart failure weighing over 85 kg (187 lbs).
Patients should be advised that initiation of treatment and (to a lesser extent) dosage
increases may be associated with transient symptoms of dizziness or lightheadedness (and rarely
syncope) within the first hour after dosing. During these periods, patients should avoid situations
such as driving or hazardous tasks, where symptoms could result in injury. Vasodilatory
symptoms often do not require treatment, but it may be useful to separate the time of dosing of
COREG from that of the ACE inhibitor or to reduce temporarily the dose of the ACE inhibitor.
The dose of COREG should not be increased until symptoms of worsening heart failure or
vasodilation have been stabilized.
Fluid retention (with or without transient worsening heart failure symptoms) should be
treated by an increase in the dose of diuretics.
2
The dose of COREG should be reduced if patients experience bradycardia (heart rate
<55 beats/minute).
Episodes of dizziness or fluid retention during initiation of COREG can generally be
managed without discontinuation of treatment and do not preclude subsequent successful
titration of, or a favorable response to, carvedilol.
2.2
Left Ventricular Dysfunction Following Myocardial Infarction
DOSAGE MUST BE INDIVIDUALIZED AND MONITORED DURING
UP-TITRATION. Treatment with COREG may be started as an inpatient or outpatient and
should be started after the patient is hemodynamically stable and fluid retention has been
minimized. It is recommended that COREG be started at 6.25 mg twice daily and increased after
3 to 10 days, based on tolerability, to 12.5 mg twice daily, then again to the target dose of 25 mg
twice daily. A lower starting dose may be used (3.125 mg twice daily) and/or the rate of
up-titration may be slowed if clinically indicated (e.g., due to low blood pressure or heart rate, or
fluid retention). Patients should be maintained on lower doses if higher doses are not tolerated.
The recommended dosing regimen need not be altered in patients who received treatment with an
IV or oral β-blocker during the acute phase of the myocardial infarction.
2.3
Hypertension
DOSAGE MUST BE INDIVIDUALIZED. The recommended starting dose of COREG
is 6.25 mg twice daily. If this dose is tolerated, using standing systolic pressure measured about
1 hour after dosing as a guide, the dose should be maintained for 7 to 14 days, and then increased
to 12.5 mg twice daily if needed, based on trough blood pressure, again using standing systolic
pressure one hour after dosing as a guide for tolerance. This dose should also be maintained for 7
to 14 days and can then be adjusted upward to 25 mg twice daily if tolerated and needed. The full
antihypertensive effect of COREG is seen within 7 to 14 days. Total daily dose should not
exceed 50 mg.
Concomitant administration with a diuretic can be expected to produce additive effects
and exaggerate the orthostatic component of carvedilol action.
2.4
Hepatic Impairment
COREG should not be given to patients with severe hepatic impairment [see
Contraindications (4)].
3
DOSAGE FORMS AND STRENGTHS
The white, oval, film-coated tablets are available in the following strengths: 3.125 mg –
engraved with 39 and SB, 6.25 mg – engraved with 4140 and SB, 12.5 mg – engraved with 4141
and SB, and 25 mg – engraved with 4142 and SB.
4
•
•
CONTRAINDICATIONS
COREG is contraindicated in the following conditions:
Bronchial asthma or related bronchospastic conditions. Deaths from status asthmaticus have
been reported following single doses of COREG.
Second- or third-degree AV block.
3
•
•
•
•
•
Sick sinus syndrome.
Severe bradycardia (unless a permanent pacemaker is in place).
Patients with cardiogenic shock or who have decompensated heart failure requiring the use of
intravenous inotropic therapy. Such patients should first be weaned from intravenous therapy
before initiating COREG.
Patients with severe hepatic impairment.
Patients with a history of a serious hypersensitivity reaction (e.g., Stevens-Johnson
syndrome, anaphylactic reaction, angioedema) to any component of this medication or other
medications containing carvedilol.
5
5.1
WARNINGS AND PRECAUTIONS
Cessation of Therapy
Patients with coronary artery disease, who are being treated with COREG, should
be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and
the occurrence of myocardial infarction and ventricular arrhythmias have been reported in
angina patients following the abrupt discontinuation of therapy with β-blockers. The last 2
complications may occur with or without preceding exacerbation of the angina pectoris. As
with other β-blockers, when discontinuation of COREG is planned, the patients should be
carefully observed and advised to limit physical activity to a minimum. COREG should be
discontinued over 1 to 2 weeks whenever possible. If the angina worsens or acute coronary
insufficiency develops, it is recommended that COREG be promptly reinstituted, at least
temporarily. Because coronary artery disease is common and may be unrecognized, it may
be prudent not to discontinue therapy with COREG abruptly even in patients treated only
for hypertension or heart failure.
5.2
Bradycardia
In clinical trials, COREG caused bradycardia in about 2% of hypertensive subjects, 9%
of heart failure subjects, and 6.5% of myocardial infarction subjects with left ventricular
dysfunction. If pulse rate drops below 55 beats/minute, the dosage should be reduced.
5.3
Hypotension
In clinical trials of primarily mild-to-moderate heart failure, hypotension and postural
hypotension occurred in 9.7% and syncope in 3.4% of subjects receiving COREG compared with
3.6% and 2.5% of placebo subjects, respectively. The risk for these events was highest during the
first 30 days of dosing, corresponding to the up-titration period and was a cause for
discontinuation of therapy in 0.7% of subjects receiving COREG, compared with 0.4% of
placebo subjects. In a long-term, placebo-controlled trial in severe heart failure (COPERNICUS),
hypotension and postural hypotension occurred in 15.1% and syncope in 2.9% of heart failure
subjects receiving COREG compared with 8.7% and 2.3% of placebo subjects, respectively.
These events were a cause for discontinuation of therapy in 1.1% of subjects receiving COREG,
compared with 0.8% of placebo subjects.
4
Postural hypotension occurred in 1.8% and syncope in 0.1% of hypertensive subjects,
primarily following the initial dose or at the time of dose increase and was a cause for
discontinuation of therapy in 1% of subjects.
In the CAPRICORN trial of survivors of an acute myocardial infarction, hypotension or
postural hypotension occurred in 20.2% of subjects receiving COREG compared with 12.6% of
placebo subjects. Syncope was reported in 3.9% and 1.9% of subjects, respectively. These events
were a cause for discontinuation of therapy in 2.5% of subjects receiving COREG, compared
with 0.2% of placebo subjects.
Starting with a low dose, administration with food, and gradual up-titration should
decrease the likelihood of syncope or excessive hypotension [see Dosage and Administration
(2.1, 2.2, 2.3)]. During initiation of therapy, the patient should be cautioned to avoid situations
such as driving or hazardous tasks, where injury could result should syncope occur.
5.4
Heart Failure/Fluid Retention
Worsening heart failure or fluid retention may occur during up-titration of carvedilol. If
such symptoms occur, diuretics should be increased and the carvedilol dose should not be
advanced until clinical stability resumes [see Dosage and Administration (2)]. Occasionally it is
necessary to lower the carvedilol dose or temporarily discontinue it. Such episodes do not
preclude subsequent successful titration of, or a favorable response to, carvedilol. In a
placebo-controlled trial of subjects with severe heart failure, worsening heart failure during the
first 3 months was reported to a similar degree with carvedilol and with placebo. When treatment
was maintained beyond 3 months, worsening heart failure was reported less frequently in
subjects treated with carvedilol than with placebo. Worsening heart failure observed during
long-term therapy is more likely to be related to the patients’ underlying disease than to
treatment with carvedilol.
5.5
Non-allergic Bronchospasm
Patients with bronchospastic disease (e.g., chronic bronchitis and emphysema) should, in
general, not receive β-blockers. COREG may be used with caution, however, in patients who do
not respond to, or cannot tolerate, other antihypertensive agents. It is prudent, if COREG is used,
to use the smallest effective dose, so that inhibition of endogenous or exogenous β-agonists is
minimized.
In clinical trials of subjects with heart failure, subjects with bronchospastic disease were
enrolled if they did not require oral or inhaled medication to treat their bronchospastic disease. In
such patients, it is recommended that carvedilol be used with caution. The dosing
recommendations should be followed closely and the dose should be lowered if any evidence of
bronchospasm is observed during up-titration.
5.6
Glycemic Control in Type 2 Diabetes
In general, β-blockers may mask some of the manifestations of hypoglycemia,
particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia
and delay recovery of serum glucose levels. Patients subject to spontaneous hypoglycemia, or
5
diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these
possibilities.
In heart failure patients with diabetes, carvedilol therapy may lead to worsening
hyperglycemia, which responds to intensification of hypoglycemic therapy. It is recommended
that blood glucose be monitored when carvedilol dosing is initiated, adjusted, or discontinued.
Trials designed to examine the effects of carvedilol on glycemic control in patients with diabetes
and heart failure have not been conducted.
In a trial designed to examine the effects of carvedilol on glycemic control in a
population with mild-to-moderate hypertension and well-controlled type 2 diabetes mellitus,
carvedilol had no adverse effect on glycemic control, based on HbA1c measurements [see
Clinical Studies (14.4)].
5.7
Peripheral Vascular Disease
β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients
with peripheral vascular disease. Caution should be exercised in such individuals.
5.8
Deterioration of Renal Function
Rarely, use of carvedilol in patients with heart failure has resulted in deterioration of
renal function. Patients at risk appear to be those with low blood pressure (systolic blood
pressure <100 mm Hg), ischemic heart disease and diffuse vascular disease, and/or underlying
renal insufficiency. Renal function has returned to baseline when carvedilol was stopped. In
patients with these risk factors it is recommended that renal function be monitored during
up-titration of carvedilol and the drug discontinued or dosage reduced if worsening of renal
function occurs.
5.9
Major Surgery
Chronically administered beta-blocking therapy should not be routinely withdrawn prior
to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic
stimuli may augment the risks of general anesthesia and surgical procedures.
5.10 Thyrotoxicosis
β-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia.
Abrupt withdrawal of β-blockade may be followed by an exacerbation of the symptoms of
hyperthyroidism or may precipitate thyroid storm.
5.11 Pheochromocytoma
In patients with pheochromocytoma, an α-blocking agent should be initiated prior to the
use of any β-blocking agent. Although carvedilol has both α- and β-blocking pharmacologic
activities, there has been no experience with its use in this condition. Therefore, caution should
be taken in the administration of carvedilol to patients suspected of having pheochromocytoma.
5.12 Prinzmetal’s Variant Angina
Agents with non-selective β-blocking activity may provoke chest pain in patients with
Prinzmetal’s variant angina. There has been no clinical experience with carvedilol in these
patients although the α-blocking activity may prevent such symptoms. However, caution should
6
be taken in the administration of carvedilol to patients suspected of having Prinzmetal’s variant
angina.
5.13 Risk of Anaphylactic Reaction
While taking β-blockers, patients with a history of severe anaphylactic reaction to a
variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or
therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat
allergic reaction.
5.14 Intraoperative Floppy Iris Syndrome
Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in
some patients treated with alpha-1 blockers (COREG is an alpha/beta blocker). This variant of
small pupil syndrome is characterized by the combination of a flaccid iris that billows in
response to intraoperative irrigation currents, progressive intraoperative miosis despite
preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the
phacoemulsification incisions. The patient’s ophthalmologist should be prepared for possible
modifications to the surgical technique, such as utilization of iris hooks, iris dilator rings, or
viscoelastic substances. There does not appear to be a benefit of stopping alpha-1 blocker
therapy prior to cataract surgery.
6
6.1
ADVERSE REACTIONS
Clinical Studies Experience
COREG has been evaluated for safety in subjects with heart failure (mild, moderate, and
severe), in subjects with left ventricular dysfunction following myocardial infarction and in
hypertensive subjects. The observed adverse event profile was consistent with the pharmacology
of the drug and the health status of the subjects in the clinical trials. Adverse events reported for
each of these patient populations are provided below. Excluded are adverse events considered
too general to be informative, and those not reasonably associated with the use of the drug
because they were associated with the condition being treated or are very common in the treated
population. Rates of adverse events were generally similar across demographic subsets (men and
women, elderly and non-elderly, blacks and non-blacks).
Heart Failure: COREG has been evaluated for safety in heart failure in more than
4,500 subjects worldwide of whom more than 2,100 participated in placebo-controlled clinical
trials. Approximately 60% of the total treated population in placebo-controlled clinical trials
received COREG for at least 6 months and 30% received COREG for at least 12 months. In the
COMET trial, 1,511 subjects with mild-to-moderate heart failure were treated with COREG for
up to 5.9 years (mean: 4.8 years). Both in US clinical trials in mild-to-moderate heart failure that
compared COREG in daily doses up to 100 mg (n = 765) with placebo (n = 437), and in a
multinational clinical trial in severe heart failure (COPERNICUS) that compared COREG in
daily doses up to 50 mg (n = 1,156) with placebo (n = 1,133), discontinuation rates for adverse
experiences were similar in carvedilol and placebo subjects. In placebo-controlled clinical trials,
7
the only cause of discontinuation >1%, and occurring more often on carvedilol was dizziness
(1.3% on carvedilol, 0.6% on placebo in the COPERNICUS trial).
Table 1 shows adverse events reported in subjects with mild-to-moderate heart failure
enrolled in US placebo-controlled clinical trials, and with severe heart failure enrolled in the
COPERNICUS trial. Shown are adverse events that occurred more frequently in drug-treated
subjects than placebo-treated subjects with an incidence of >3% in subjects treated with
carvedilol regardless of causality. Median trial medication exposure was 6.3 months for both
carvedilol and placebo subjects in the trials of mild-to-moderate heart failure, and 10.4 months in
the trial of severe heart failure subjects. The adverse event profile of COREG observed in the
long-term COMET trial was generally similar to that observed in the US Heart Failure Trials.
8
Table 1. Adverse Events (%) Occurring More Frequently With COREG Than With
Placebo in Subjects With Mild-to-Moderate Heart Failure (HF) Enrolled in US Heart
Failure Trials or in Subjects With Severe Heart Failure in the COPERNICUS Trial
(Incidence >3% in Subjects Treated With Carvedilol, Regardless of Causality)
Mild-to-Moderate HF
Severe HF
COREG
Placebo
Body System/
COREG
Placebo
Adverse Event
(n = 765)
(n = 437)
(n = 1,156)
(n = 1,133)
Body as a Whole
Asthenia
7
7
11
9
Fatigue
24
22
—
—
Digoxin level increased
5
4
2
1
Edema generalized
5
3
6
5
Edema dependent
4
2
—
—
Cardiovascular
Bradycardia
9
1
10
3
Hypotension
9
3
14
8
Syncope
3
3
8
5
Angina pectoris
2
3
6
4
Central Nervous System
Dizziness
32
19
24
17
Headache
8
7
5
3
Gastrointestinal
Diarrhea
12
6
5
3
Nausea
9
5
4
3
Vomiting
6
4
1
2
Metabolic
Hyperglycemia
12
8
5
3
Weight increase
10
7
12
11
BUN increased
6
5
—
—
NPN increased
6
5
—
—
Hypercholesterolemia
4
3
1
1
Edema peripheral
2
1
7
6
Musculoskeletal
Arthralgia
6
5
1
1
Respiratory
Cough increased
8
9
5
4
Rales
4
4
4
2
Vision
Vision abnormal
5
2
—
—
9
Cardiac failure and dyspnea were also reported in these trials, but the rates were equal or
greater in subjects who received placebo.
The following adverse events were reported with a frequency of >1% but ≤3% and more
frequently with COREG in either the US placebo-controlled trials in subjects with
mild-to-moderate heart failure, or in subjects with severe heart failure in the COPERNICUS trial.
Incidence >1% to ≤3%
Body as a Whole: Allergy, malaise, hypovolemia, fever, leg edema.
Cardiovascular: Fluid overload, postural hypotension, aggravated angina pectoris,
AV block, palpitation, hypertension.
Central and Peripheral Nervous System: Hypesthesia, vertigo, paresthesia.
Gastrointestinal: Melena, periodontitis.
Liver and Biliary System: SGPT increased, SGOT increased.
Metabolic and Nutritional: Hyperuricemia, hypoglycemia, hyponatremia, increased
alkaline phosphatase, glycosuria, hypervolemia, diabetes mellitus, GGT increased, weight loss,
hyperkalemia, creatinine increased.
Musculoskeletal: Muscle cramps.
Platelet, Bleeding, and Clotting: Prothrombin decreased, purpura,
thrombocytopenia.
Psychiatric: Somnolence.
Reproductive, male: Impotence.
Special Senses: Blurred vision.
Urinary System: Renal insufficiency, albuminuria, hematuria.
Left Ventricular Dysfunction Following Myocardial Infarction: COREG has been
evaluated for safety in survivors of an acute myocardial infarction with left ventricular
dysfunction in the CAPRICORN trial which involved 969 subjects who received COREG and
980 who received placebo. Approximately 75% of the subjects received COREG for at least
6 months and 53% received COREG for at least 12 months. Subjects were treated for an average
of 12.9 months and 12.8 months with COREG and placebo, respectively.
The most common adverse events reported with COREG in the CAPRICORN trial were
consistent with the profile of the drug in the US heart failure trials and the COPERNICUS trial.
The only additional adverse events reported in CAPRICORN in >3% of the subjects and more
commonly on carvedilol were dyspnea, anemia, and lung edema. The following adverse events
were reported with a frequency of >1% but ≤3% and more frequently with COREG: flu
syndrome, cerebrovascular accident, peripheral vascular disorder, hypotonia, depression,
gastrointestinal pain, arthritis, and gout. The overall rates of discontinuations due to adverse
events were similar in both groups of subjects. In this database, the only cause of discontinuation
>1%, and occurring more often on carvedilol was hypotension (1.5% on carvedilol, 0.2% on
placebo).
Hypertension: COREG has been evaluated for safety in hypertension in more than
2,193 subjects in US clinical trials and in 2,976 subjects in international clinical trials.
10
Approximately 36% of the total treated population received COREG for at least 6 months. Most
adverse events reported during therapy with COREG were of mild to moderate severity. In US
controlled clinical trials directly comparing COREG in doses up to 50 mg (n = 1,142) with
placebo (n = 462), 4.9% of subjects receiving COREG discontinued for adverse events versus
5.2% of placebo subjects. Although there was no overall difference in discontinuation rates,
discontinuations were more common in the carvedilol group for postural hypotension (1% versus
0). The overall incidence of adverse events in US placebo-controlled trials increased with
increasing dose of COREG. For individual adverse events this could only be distinguished for
dizziness, which increased in frequency from 2% to 5% as total daily dose increased from
6.25 mg to 50 mg.
Table 2 shows adverse events in US placebo-controlled clinical trials for hypertension
that occurred with an incidence of ≥1% regardless of causality, and that were more frequent in
drug-treated subjects than placebo-treated subjects.
Table 2. Adverse Events (%) Occurring in US Placebo-Controlled Hypertension Trials
(Incidence ≥1%, Regardless of Causality)a
COREG
Placebo
Body System/
Adverse Event
(n = 1,142)
(n = 462)
Cardiovascular
Bradycardia
2
—
Postural hypotension
2
—
Peripheral edema
1
—
Central Nervous System
Dizziness
6
5
Insomnia
2
1
Gastrointestinal
Diarrhea
2
1
Hematologic
Thrombocytopenia
1
—
Metabolic
Hypertriglyceridemia
1
—
a
Shown are events with rate >1% rounded to nearest integer.
Dyspnea and fatigue were also reported in these trials, but the rates were equal or greater
in subjects who received placebo.
The following adverse events not described above were reported as possibly or probably
related to COREG in worldwide open or controlled trials with COREG in subjects with
hypertension or heart failure.
Incidence >0.1% to ≤1%
Cardiovascular: Peripheral ischemia, tachycardia.
11
Central and Peripheral Nervous System: Hypokinesia.
Gastrointestinal: Bilirubinemia, increased hepatic enzymes (0.2% of hypertension
patients and 0.4% of heart failure patients were discontinued from therapy because of increases
in hepatic enzymes) [see Adverse Reactions (6.2)].
Psychiatric: Nervousness, sleep disorder, aggravated depression, impaired
concentration, abnormal thinking, paroniria, emotional lability.
Respiratory System: Asthma [see Contraindications (4)].
Reproductive, male: Decreased libido.
Skin and Appendages: Pruritus, rash erythematous, rash maculopapular, rash
psoriaform, photosensitivity reaction.
Special Senses: Tinnitus.
Urinary System: Micturition frequency increased.
Autonomic Nervous System: Dry mouth, sweating increased.
Metabolic and Nutritional: Hypokalemia, hypertriglyceridemia.
Hematologic: Anemia, leukopenia.
The following events were reported in ≤0.1% of subjects and are potentially important:
complete AV block, bundle branch block, myocardial ischemia, cerebrovascular disorder,
convulsions, migraine, neuralgia, paresis, anaphylactoid reaction, alopecia, exfoliative
dermatitis, amnesia, GI hemorrhage, bronchospasm, pulmonary edema, decreased hearing,
respiratory alkalosis, increased BUN, decreased HDL, pancytopenia, and atypical lymphocytes.
6.2
Laboratory Abnormalities
Reversible elevations in serum transaminases (ALT or AST) have been observed during
treatment with COREG. Rates of transaminase elevations (2 to 3 times the upper limit of normal)
observed during controlled clinical trials have generally been similar between subjects treated
with COREG and those treated with placebo. However, transaminase elevations, confirmed by
rechallenge, have been observed with COREG. In a long-term, placebo-controlled trial in severe
heart failure, subjects treated with COREG had lower values for hepatic transaminases than
subjects treated with placebo, possibly because improvements in cardiac function induced by
COREG led to less hepatic congestion and/or improved hepatic blood flow.
COREG has not been associated with clinically significant changes in serum potassium,
total triglycerides, total cholesterol, HDL cholesterol, uric acid, blood urea nitrogen, or
creatinine. No clinically relevant changes were noted in fasting serum glucose in hypertensive
patients; fasting serum glucose was not evaluated in the heart failure clinical trials.
6.3
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of
COREG. Because these reactions are reported voluntarily from a population of uncertain size, it
is not always possible to reliably estimate their frequency or establish a causal relationship to
drug exposure.
Blood and Lymphatic System Disorders: Aplastic anemia.
12
Immune System Disorders: Hypersensitivity (e.g., anaphylactic reactions, angioedema,
urticaria).
Renal and Urinary Disorders: Urinary incontinence.
Respiratory, Thoracic, and Mediastinal Disorders: Interstitial pneumonitis.
Skin and Subcutaneous Tissue Disorders: Stevens-Johnson syndrome, toxic
epidermal necrolysis, erythema multiforme.
7
7.1
DRUG INTERACTIONS
CYP2D6 Inhibitors and Poor Metabolizers
Interactions of carvedilol with potent inhibitors of CYP2D6 isoenzyme (such as
quinidine, fluoxetine, paroxetine, and propafenone) have not been studied, but these drugs would
be expected to increase blood levels of the R(+) enantiomer of carvedilol [see Clinical
Pharmacology (12.3)]. Retrospective analysis of side effects in clinical trials showed that poor
2D6 metabolizers had a higher rate of dizziness during up-titration, presumably resulting from
vasodilating effects of the higher concentrations of the α-blocking R(+) enantiomer.
7.2
Hypotensive Agents
Patients taking both agents with β-blocking properties and a drug that can deplete
catecholamines (e.g., reserpine and monoamine oxidase inhibitors) should be observed closely
for signs of hypotension and/or severe bradycardia.
Concomitant administration of clonidine with agents with β-blocking properties may
potentiate blood-pressure- and heart-rate-lowering effects. When concomitant treatment with
agents with β-blocking properties and clonidine is to be terminated, the β-blocking agent should
be discontinued first. Clonidine therapy can then be discontinued several days later by gradually
decreasing the dosage.
7.3
Cyclosporine
Modest increases in mean trough cyclosporine concentrations were observed following
initiation of carvedilol treatment in 21 renal transplant subjects suffering from chronic vascular
rejection. In about 30% of subjects, the dose of cyclosporine had to be reduced in order to
maintain cyclosporine concentrations within the therapeutic range, while in the remainder no
adjustment was needed. On the average for the group, the dose of cyclosporine was reduced
about 20% in these subjects. Due to wide interindividual variability in the dose adjustment
required, it is recommended that cyclosporine concentrations be monitored closely after initiation
of carvedilol therapy and that the dose of cyclosporine be adjusted as appropriate.
7.4
Digitalis Glycosides
Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease
heart rate. Concomitant use can increase the risk of bradycardia. Digoxin concentrations are
increased by about 15% when digoxin and carvedilol are administered concomitantly. Therefore,
increased monitoring of digoxin is recommended when initiating, adjusting, or discontinuing
COREG [see Clinical Pharmacology (12.5)].
13
7.5
Inducers/Inhibitors of Hepatic Metabolism
Rifampin reduced plasma concentrations of carvedilol by about 70% [see Clinical
Pharmacology (12.5)]. Cimetidine increased AUC by about 30% but caused no change in Cmax
[see Clinical Pharmacology (12.5)].
7.6
Amiodarone
Amiodarone, and its metabolite desethyl amiodarone, inhibitors of CYP2C9 and Pglycoprotein, increased concentrations of the S(-)-enantiomer of carvedilol by at least 2-fold [see
Clinical Pharmacology (12.5)]. The concomitant administration of amiodarone or other CYP2C9
inhibitors such as fluconazole with COREG may enhance the β-blocking properties of carvedilol
resulting in further slowing of the heart rate or cardiac conduction. Patients should be observed
for signs of bradycardia or heart block, particularly when one agent is added to pre-existing
treatment with the other.
7.7
Calcium Channel Blockers
Conduction disturbance (rarely with hemodynamic compromise) has been observed when
COREG is co-administered with diltiazem. As with other agents with β-blocking properties, if
COREG is to be administered with calcium channel blockers of the verapamil or diltiazem type,
it is recommended that ECG and blood pressure be monitored.
7.8
Insulin or Oral Hypoglycemics
Agents with β-blocking properties may enhance the blood-sugar-reducing effect of
insulin and oral hypoglycemics. Therefore, in patients taking insulin or oral hypoglycemics,
regular monitoring of blood glucose is recommended [see Warnings and Precautions (5.6)].
7.9
Anesthesia
If treatment with COREG is to be continued perioperatively, particular care should be
taken when anesthetic agents which depress myocardial function, such as ether, cyclopropane,
and trichloroethylene, are used [see Overdosage (10)].
8
8.1
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Studies performed in pregnant rats and rabbits given carvedilol
revealed increased post-implantation loss in rats at doses of 300 mg/kg/day (50 times the
maximum recommended human dose [MRHD] as mg/m2) and in rabbits at doses of
75 mg/kg/day (25 times the MRHD as mg/m2). In the rats, there was also a decrease in fetal body
weight at the maternally toxic dose of 300 mg/kg/day (50 times the MRHD as mg/m2), which
was accompanied by an elevation in the frequency of fetuses with delayed skeletal development
(missing or stunted 13th rib). In rats the no-observed-effect level for developmental toxicity was
60 mg/kg/day (10 times the MRHD as mg/m2); in rabbits it was 15 mg/kg/day (5 times the
MRHD as mg/m2). There are no adequate and well-controlled studies in pregnant women.
COREG should be used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
14
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Studies in rats have shown
that carvedilol and/or its metabolites (as well as other β-blockers) cross the placental barrier and
are excreted in breast milk. There was increased mortality at one week post-partum in neonates
from rats treated with 60 mg/kg/day (10 times the MRHD as mg/m2) and above during the last
trimester through day 22 of lactation. Because many drugs are excreted in human milk and
because of the potential for serious adverse reactions in nursing infants from β-blockers,
especially bradycardia, a decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the drug to the mother. The effects of
other α- and β-blocking agents have included perinatal and neonatal distress.
8.4
Pediatric Use
Effectiveness of COREG in patients younger than 18 years has not been established.
In a double-blind trial, 161 children (mean age: 6 years, range: 2 months to 17 years; 45%
younger than 2 years) with chronic heart failure [NYHA class II-IV, left ventricular ejection
fraction <40% for children with a systemic left ventricle (LV), and moderate-severe ventricular
dysfunction qualitatively by echo for those with a systemic ventricle that was not an LV] who
were receiving standard background treatment were randomized to placebo or to 2 dose levels of
carvedilol. These dose levels produced placebo-corrected heart rate reduction of 4 to 6 heart
beats per minute, indicative of β-blockade activity. Exposure appeared to be lower in pediatric
subjects than adults. After 8 months of follow-up, there was no significant effect of treatment on
clinical outcomes. Adverse reactions in this trial that occurred in greater than 10% of subjects
treated with COREG and at twice the rate of placebo-treated subjects included chest pain (17%
versus 6%), dizziness (13% versus 2%), and dyspnea (11% versus 0%).
8.5
Geriatric Use
Of the 765 subjects with heart failure randomized to COREG in US clinical trials, 31%
(235) were 65 years of age or older, and 7.3% (56) were 75 years of age or older. Of the
1,156 subjects randomized to COREG in a long-term, placebo-controlled trial in severe heart
failure, 47% (547) were 65 years of age or older, and 15% (174) were 75 years of age or older.
Of 3,025 subjects receiving COREG in heart failure trials worldwide, 42% were 65 years of age
or older.
Of the 975 myocardial infarction subjects randomized to COREG in the CAPRICORN
trial, 48% (468) were 65 years of age or older, and 11% (111) were 75 years of age or older.
Of the 2,065 hypertensive subjects in US clinical trials of efficacy or safety who were
treated with COREG, 21% (436) were 65 years of age or older. Of 3,722 subjects receiving
COREG in hypertension clinical trials conducted worldwide, 24% were 65 years of age or older.
With the exception of dizziness in hypertensive subjects (incidence 8.8% in the elderly
versus 6% in younger subjects), no overall differences in the safety or effectiveness (see Figures
2 and 4) were observed between the older subjects and younger subjects in each of these
populations. Similarly, other reported clinical experience has not identified differences in
15
responses between the elderly and younger subjects, but greater sensitivity of some older
individuals cannot be ruled out.
10
OVERDOSAGE
Overdosage may cause severe hypotension, bradycardia, cardiac insufficiency,
cardiogenic shock, and cardiac arrest. Respiratory problems, bronchospasms, vomiting, lapses of
consciousness, and generalized seizures may also occur.
The patient should be placed in a supine position and, where necessary, kept under
observation and treated under intensive-care conditions. Gastric lavage or pharmacologically
induced emesis may be used shortly after ingestion. The following agents may be administered:
For excessive bradycardia: Atropine, 2 mg IV.
To support cardiovascular function: Glucagon, 5 to 10 mg IV rapidly over 30 seconds,
followed by a continuous infusion of 5 mg/hour; sympathomimetics (dobutamine, isoprenaline,
adrenaline) at doses according to body weight and effect.
If peripheral vasodilation dominates, it may be necessary to administer adrenaline or
noradrenaline with continuous monitoring of circulatory conditions. For therapy-resistant
bradycardia, pacemaker therapy should be performed. For bronchospasm, β-sympathomimetics
(as aerosol or IV) or aminophylline IV should be given. In the event of seizures, slow IV
injection of diazepam or clonazepam is recommended.
NOTE: In the event of severe intoxication where there are symptoms of shock, treatment
with antidotes must be continued for a sufficiently long period of time consistent with the 7- to
10-hour half-life of carvedilol.
Cases of overdosage with COREG alone or in combination with other drugs have been
reported. Quantities ingested in some cases exceeded 1,000 milligrams. Symptoms experienced
included low blood pressure and heart rate. Standard supportive treatment was provided and
individuals recovered.
11
DESCRIPTION
Carvedilol is a nonselective β-adrenergic blocking agent with α1-blocking activity. It is
(±)-1-(Carbazol-4-yloxy)-3-[[2-(o-methoxyphenoxy)ethyl]amino]-2-propanol. Carvedilol is a
racemic mixture with the following structure:
COREG is a white, oval, film-coated tablet containing 3.125 mg, 6.25 mg, 12.5 mg, or
25 mg of carvedilol. The 6.25-mg, 12.5-mg, and 25-mg tablets are TILTAB® tablets. Inactive
ingredients consist of colloidal silicon dioxide, crospovidone, hypromellose, lactose, magnesium
stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and titanium dioxide.
16
Carvedilol is a white to off-white powder with a molecular weight of 406.5 and a
molecular formula of C24H26N2O4. It is freely soluble in dimethylsulfoxide; soluble in methylene
chloride and methanol; sparingly soluble in 95% ethanol and isopropanol; slightly soluble in
ethyl ether; and practically insoluble in water, gastric fluid (simulated, TS, pH 1.1), and intestinal
fluid (simulated, TS without pancreatin, pH 7.5).
12
12.1
CLINICAL PHARMACOLOGY
Mechanism of Action
COREG is a racemic mixture in which nonselective β-adrenoreceptor blocking activity is
present in the S(-) enantiomer and α1-adrenergic blocking activity is present in both R(+) and
S(-) enantiomers at equal potency. COREG has no intrinsic sympathomimetic activity.
12.2 Pharmacodynamics
Heart Failure: The basis for the beneficial effects of COREG in heart failure is not
established.
Two placebo-controlled trials compared the acute hemodynamic effects of COREG with
baseline measurements in 59 and 49 subjects with NYHA class II-IV heart failure receiving
diuretics, ACE inhibitors, and digitalis. There were significant reductions in systemic blood
pressure, pulmonary artery pressure, pulmonary capillary wedge pressure, and heart rate. Initial
effects on cardiac output, stroke volume index, and systemic vascular resistance were small and
variable.
These trials measured hemodynamic effects again at 12 to 14 weeks. COREG
significantly reduced systemic blood pressure, pulmonary artery pressure, right atrial pressure,
systemic vascular resistance, and heart rate, while stroke volume index was increased.
Among 839 subjects with NYHA class II-III heart failure treated for 26 to 52 weeks in
4 US placebo-controlled trials, average left ventricular ejection fraction (EF) measured by
radionuclide ventriculography increased by 9 EF units (%) in subjects receiving COREG and by
2 EF units in placebo subjects at a target dose of 25 to 50 mg twice daily. The effects of
carvedilol on ejection fraction were related to dose. Doses of 6.25 mg twice daily, 12.5 mg twice
daily, and 25 mg twice daily were associated with placebo-corrected increases in EF of 5 EF
units, 6 EF units, and 8 EF units, respectively; each of these effects were nominally statistically
significant.
Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the
beneficial effects of COREG in patients with left ventricular dysfunction following an acute
myocardial infarction is not established.
Hypertension: The mechanism by which β-blockade produces an antihypertensive effect
has not been established.
β-adrenoreceptor blocking activity has been demonstrated in animal and human studies
showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exerciseand/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia.
Significant β-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration.
17
α1-adrenoreceptor blocking activity has been demonstrated in human and animal studies,
showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes
vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the
reduction of blood pressure and usually are seen within 30 minutes of drug administration.
Due to the α1-receptor blocking activity of carvedilol, blood pressure is lowered more in
the standing than in the supine position, and symptoms of postural hypotension (1.8%), including
rare instances of syncope, can occur. Following oral administration, when postural hypotension
has occurred, it has been transient and is uncommon when COREG is administered with food at
the recommended starting dose and titration increments are closely followed [see Dosage and
Administration (2)].
In hypertensive patients with normal renal function, therapeutic doses of COREG
decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma
flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive
patients with normal renal function were similar after COREG and placebo.
COREG has little effect on plasma catecholamines, plasma aldosterone, or electrolyte
levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It
also increases levels of atrial natriuretic peptide.
12.3 Pharmacokinetics
COREG is rapidly and extensively absorbed following oral administration, with absolute
bioavailability of approximately 25% to 35% due to a significant degree of first-pass
metabolism. Following oral administration, the apparent mean terminal elimination half-life of
carvedilol generally ranges from 7 to 10 hours. Plasma concentrations achieved are proportional
to the oral dose administered. When administered with food, the rate of absorption is slowed, as
evidenced by a delay in the time to reach peak plasma levels, with no significant difference in
extent of bioavailability. Taking COREG with food should minimize the risk of orthostatic
hypotension.
Carvedilol is extensively metabolized. Following oral administration of radiolabelled
carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity
in plasma as measured by area under the curve (AUC). Less than 2% of the dose was excreted
unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and
glucuronidation. The oxidative metabolites are further metabolized by conjugation via
glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily via the bile
into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites
with β-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite
is approximately 13 times more potent than carvedilol for β-blockade.
Compared with carvedilol, the 3 active metabolites exhibit weak vasodilating activity.
Plasma concentrations of the active metabolites are about one-tenth of those observed for
carvedilol and have pharmacokinetics similar to the parent.
Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of
R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral
18
administration in healthy subjects. The mean apparent terminal elimination half-lives for
R(+)-carvedilol range from 5 to 9 hours compared with 7 to 11 hours for the S(-)-enantiomer.
The primary P450 enzymes responsible for the metabolism of both R(+) and
S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent
CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4’- and
5’-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be
of primary importance in the O-methylation pathway of S(-)-carvedilol.
Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of
debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma
concentrations of R(+)-carvedilol compared with extensive metabolizers. In contrast, plasma
levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating
this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol.
The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of
S-mephenytoin (patients deficient in cytochrome P450 2C19).
Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The
plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is
a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L,
indicating substantial distribution into extravascular tissues. Plasma clearance ranges from 500 to
700 mL/min.
12.4 Specific Populations
Heart Failure: Steady-state plasma concentrations of carvedilol and its enantiomers
increased proportionally over the 6.25 to 50 mg dose range in subjects with heart failure.
Compared with healthy subjects, heart failure subjects had increased mean AUC and Cmax values
for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 subjects
with NYHA class IV heart failure. The mean apparent terminal elimination half-life for
carvedilol was similar to that observed in healthy subjects.
Geriatric: Plasma levels of carvedilol average about 50% higher in the elderly compared
with young subjects.
Hepatic Impairment: Compared with healthy subjects, patients with severe liver
impairment (cirrhosis) exhibit a 4- to 7-fold increase in carvedilol levels. Carvedilol is
contraindicated in patients with severe liver impairment.
Renal Impairment: Although carvedilol is metabolized primarily by the liver, plasma
concentrations of carvedilol have been reported to be increased in patients with renal
impairment. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations
of carvedilol were observed in hypertensive subjects with moderate to severe renal impairment
compared to a control group of hypertensive subjects with normal renal function. However, the
ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were
less pronounced, approximately 12% to 26% higher in subjects with impaired renal function.
Consistent with its high degree of plasma protein-binding, carvedilol does not appear to
be cleared significantly by hemodialysis.
19
12.5
Drug-Drug Interactions
Since carvedilol undergoes substantial oxidative metabolism, the metabolism and
pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450
enzymes.
Amiodarone: In a pharmacokinetic trial conducted in 106 Japanese subjects with heart
failure, coadministration of small loading and maintenance doses of amiodarone with carvedilol
resulted in at least a 2-fold increase in the steady-state trough concentrations of S(-)-carvedilol
[see Drug Interactions (7.6)].
Cimetidine: In a pharmacokinetic trial conducted in 10 healthy male subjects, cimetidine
(1,000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change in Cmax
[see Drug Interactions (7.5)].
Digoxin: Following concomitant administration of carvedilol (25 mg once daily) and
digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin
were increased by 14% and 16%, respectively, in 12 hypertensive subjects [see Drug
Interactions (7.4)].
Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg once
daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic
interaction for either compound.
Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the
pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 subjects with
hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.
Rifampin: In a pharmacokinetic trial conducted in 8 healthy male subjects, rifampin
(600 mg daily for 12 days) decreased the AUC and Cmax of carvedilol by about 70% [see Drug
Interactions (7.5)].
Torsemide: In a trial of 12 healthy subjects, combined oral administration of carvedilol
25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant
differences in their pharmacokinetics compared with administration of the drugs alone.
Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state
prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin
following concomitant administration with warfarin in 9 healthy volunteers.
13
13.1
NONCLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility
In 2-year studies conducted in rats given carvedilol at doses up to 75 mg/kg/day (12 times
the MRHD when compared on a mg/m2 basis) or in mice given up to 200 mg/kg/day (16 times
the MRHD on a mg/m2 basis), carvedilol had no carcinogenic effect.
Carvedilol was negative when tested in a battery of genotoxicity assays, including the
Ames and the CHO/HGPRT assays for mutagenicity and the in vitro hamster micronucleus and
in vivo human lymphocyte cell tests for clastogenicity.
20
At doses ≥200 mg/kg/day (≥32 times the MRHD as mg/m2) carvedilol was toxic to adult
rats (sedation, reduced weight gain) and was associated with a reduced number of successful
matings, prolonged mating time, significantly fewer corpora lutea and implants per dam, and
complete resorption of 18% of the litters. The no-observed-effect dose level for overt toxicity
and impairment of fertility was 60 mg/kg/day (10 times the MRHD as mg/m2).
14
14.1
CLINICAL STUDIES
Heart Failure
A total of 6,975 subjects with mild to severe heart failure were evaluated in
placebo-controlled trials of carvedilol.
Mild-to-Moderate Heart Failure: Carvedilol was studied in 5 multicenter,
placebo-controlled trials, and in 1 active-controlled trial (COMET trial) involving subjects with
mild-to-moderate heart failure.
Four US multicenter, double-blind, placebo-controlled trials enrolled 1,094 subjects
(696 randomized to carvedilol) with NYHA class II-III heart failure and ejection fraction ≤0.35.
The vast majority were on digitalis, diuretics, and an ACE inhibitor at trial entry. Patients were
assigned to the trials based upon exercise ability. An Australia-New Zealand double-blind,
placebo-controlled trial enrolled 415 subjects (half randomized to carvedilol) with less severe
heart failure. All protocols excluded subjects expected to undergo cardiac transplantation during
the 7.5 to 15 months of double-blind follow-up. All randomized subjects had tolerated a 2-week
course on carvedilol 6.25 mg twice daily.
In each trial, there was a primary end point, either progression of heart failure (1 US trial)
or exercise tolerance (2 US trials meeting enrollment goals and the Australia-New Zealand trial).
There were many secondary end points specified in these trials, including NYHA classification,
patient and physician global assessments, and cardiovascular hospitalization. Other analyses not
prospectively planned included the sum of deaths and total cardiovascular hospitalizations. In
situations where the primary end points of a trial do not show a significant benefit of treatment,
assignment of significance values to the other results is complex, and such values need to be
interpreted cautiously.
The results of the US and Australia-New Zealand trials were as follows:
Slowing Progression of Heart Failure: One US multicenter trial (366 subjects) had as its
primary end point the sum of cardiovascular mortality, cardiovascular hospitalization, and
sustained increase in heart failure medications. Heart failure progression was reduced, during an
average follow-up of 7 months, by 48% (P = 0.008).
In the Australia-New Zealand trial, death and total hospitalizations were reduced by
about 25% over 18 to 24 months. In the 3 largest US trials, death and total hospitalizations were
reduced by 19%, 39%, and 49%, nominally statistically significant in the last 2 trials. The
Australia-New Zealand results were statistically borderline.
Functional Measures: None of the multicenter trials had NYHA classification as a
primary end point, but all such trials had it as a secondary end point. There was at least a trend
21
toward improvement in NYHA class in all trials. Exercise tolerance was the primary end point in
3 trials; in none was a statistically significant effect found.
Subjective Measures: Health-related quality of life, as measured with a standard
questionnaire (a primary end point in 1 trials), was unaffected by carvedilol. However, patients’
and investigators’ global assessments showed significant improvement in most trials.
Mortality: Death was not a pre-specified end point in any trial, but was analyzed in all
trials. Overall, in these 4 US trials, mortality was reduced, nominally significantly so in 2 trials.
COMET Trial: In this double-blind trial, 3,029 subjects with NYHA class II-IV heart
failure (left ventricular ejection fraction ≤35%) were randomized to receive either carvedilol
(target dose: 25 mg twice daily) or immediate-release metoprolol tartrate (target dose: 50 mg
twice daily). The mean age of the subjects was approximately 62 years, 80% were males, and the
mean left ventricular ejection fraction at baseline was 26%. Approximately 96% of the subjects
had NYHA class II or III heart failure. Concomitant treatment included diuretics (99%), ACE
inhibitors (91%), digitalis (59%), aldosterone antagonists (11%), and “statin” lipid-lowering
agents (21%). The mean duration of follow-up was 4.8 years. The mean dose of carvedilol was
42 mg per day.
The trial had 2 primary end points: all-cause mortality and the composite of death plus
hospitalization for any reason. The results of COMET are presented in Table 3 below. All-cause
mortality carried most of the statistical weight and was the primary determinant of the trial size.
All-cause mortality was 34% in the subjects treated with carvedilol and was 40% in the
immediate-release metoprolol group (P = 0.0017; hazard ratio = 0.83, 95%CI: 0.74 to 0.93). The
effect on mortality was primarily due to a reduction in cardiovascular death. The difference
between the 2 groups with respect to the composite end point was not significant (P = 0.122).
The estimated mean survival was 8.0 years with carvedilol and 6.6 years with immediate-release
metoprolol.
Table 3. Results of COMET
End point
All-cause mortality
Mortality + all hospitalization
Cardiovascular death
Sudden death
Death due to circulatory failure
Death due to stroke
Carvedilol
N = 1,511
34%
74%
30%
14%
11%
0.9%
Metoprolol
N = 1,518
40%
76%
35%
17%
13%
2.5%
Hazard ratio
0.83
0.94
0.80
0.81
0.83
0.33
(95% CI)
0.74 – 0.93
0.86 – 1.02
0.70 – 0.90
0.68 – 0.97
0.67 – 1.02
0.18 – 0.62
It is not known whether this formulation of metoprolol at any dose or this low dose of
metoprolol in any formulation has any effect on survival or hospitalization in patients with heart
failure. Thus, this trial extends the time over which carvedilol manifests benefits on survival in
22
heart failure, but it is not evidence that carvedilol improves outcome over the formulation of
metoprolol (TOPROL-XL®) with benefits in heart failure.
Severe Heart Failure (COPERNICUS): In a double-blind trial (COPERNICUS),
2,289 subjects with heart failure at rest or with minimal exertion and left ventricular ejection
fraction <25% (mean 20%), despite digitalis (66%), diuretics (99%), and ACE inhibitors (89%)
were randomized to placebo or carvedilol. Carvedilol was titrated from a starting dose of
3.125 mg twice daily to the maximum tolerated dose or up to 25 mg twice daily over a minimum
of 6 weeks. Most subjects achieved the target dose of 25 mg. The trial was conducted in Eastern
and Western Europe, the United States, Israel, and Canada. Similar numbers of subjects per
group (about 100) withdrew during the titration period.
The primary end point of the trial was all-cause mortality, but cause-specific mortality
and the risk of death or hospitalization (total, cardiovascular [CV], or heart failure [HF]) were
also examined. The developing trial data were followed by a data monitoring committee, and
mortality analyses were adjusted for these multiple looks. The trial was stopped after a median
follow-up of 10 months because of an observed 35% reduction in mortality (from 19.7% per
patient-year on placebo to 12.8% on carvedilol, hazard ratio 0.65, 95% CI: 0.52 to 0.81,
P = 0.0014, adjusted) (see Figure 1). The results of COPERNICUS are shown in Table 4.
Table 4. Results of COPERNICUS Trial in Subjects With Severe Heart Failure
Placebo
Carvedilol
Hazard ratio
%
End point
(N = 1,133) (N = 1,156)
(95% CI)
Reduction
Mortality
190
130
0.65
35
(0.52 – 0.81)
Mortality + all
507
425
0.76
24
hospitalization
(0.67 – 0.87)
Mortality + CV
395
314
0.73
27
hospitalization
(0.63 – 0.84)
Mortality + HF
357
271
0.69
31
hospitalization
(0.59 – 0.81)
Cardiovascular = CV; Heart failure = HF.
23
Nominal
P value
0.00013
0.00004
0.00002
0.000004
Figure 1. Survival Analysis for COPERNICUS (Intent-to-Treat)
The effect on mortality was principally the result of a reduction in the rate of sudden
death among subjects without worsening heart failure.
Patients' global assessments, in which carvedilol-treated subjects were compared with
placebo, were based on pre-specified, periodic patient self-assessments regarding whether
clinical status post-treatment showed improvement, worsening or no change compared with
baseline. Subjects treated with carvedilol showed significant improvements in global
assessments compared with those treated with placebo in COPERNICUS.
The protocol also specified that hospitalizations would be assessed. Fewer subjects on
COREG than on placebo were hospitalized for any reason (372 versus 432, P = 0.0029), for
cardiovascular reasons (246 versus 314, P = 0.0003), or for worsening heart failure (198 versus
268, P = 0.0001).
COREG had a consistent and beneficial effect on all-cause mortality as well as the
combined end points of all-cause mortality plus hospitalization (total, CV, or for heart failure) in
the overall trial population and in all subgroups examined, including men and women, elderly
and non-elderly, blacks and non-blacks, and diabetics and non-diabetics (see Figure 2).
Figure 2. Effects on Mortality for Subgroups in COPERNICUS
24
14.2
Left Ventricular Dysfunction Following Myocardial Infarction
CAPRICORN was a double-blind trial comparing carvedilol and placebo in
1,959 subjects with a recent myocardial infarction (within 21 days) and left ventricular ejection
fraction of ≤40%, with (47%) or without symptoms of heart failure. Subjects given carvedilol
received 6.25 mg twice daily, titrated as tolerated to 25 mg twice daily. Subjects had to have a
systolic blood pressure >90 mm Hg, a sitting heart rate >60 beats/minute, and no
contraindication to β-blocker use. Treatment of the index infarction included aspirin (85%), IV
or oral β-blockers (37%), nitrates (73%), heparin (64%), thrombolytics (40%), and acute
angioplasty (12%). Background treatment included ACE inhibitors or angiotensin receptor
blockers (97%), anticoagulants (20%), lipid-lowering agents (23%), and diuretics (34%).
Baseline population characteristics included an average age of 63 years, 74% male, 95%
Caucasian, mean blood pressure 121/74 mm Hg, 22% with diabetes, and 54% with a history of
hypertension. Mean dosage achieved of carvedilol was 20 mg twice daily; mean duration of
follow-up was 15 months.
All-cause mortality was 15% in the placebo group and 12% in the carvedilol group,
indicating a 23% risk reduction in subjects treated with carvedilol (95% CI: 2% to 40%,
P = 0.03), as shown in Figure 3. The effects on mortality in various subgroups are shown in
Figure 4. Nearly all deaths were cardiovascular (which were reduced by 25% by carvedilol), and
most of these deaths were sudden or related to pump failure (both types of death were reduced by
carvedilol). Another trial end point, total mortality and all-cause hospitalization, did not show a
significant improvement.
There was also a significant 40% reduction in fatal or non-fatal myocardial infarction
observed in the group treated with carvedilol (95% CI: 11% to 60%, P = 0.01). A similar
reduction in the risk of myocardial infarction was also observed in a meta-analysis of placebocontrolled trials of carvedilol in heart failure.
25
Figure 3. Survival Analysis for CAPRICORN (Intent-to-Treat)
Figure 4. Effects on Mortality for Subgroups in CAPRICORN
14.3
Hypertension
COREG was studied in 2 placebo-controlled trials that utilized twice-daily dosing, at
total daily doses of 12.5 to 50 mg. In these and other trials, the starting dose did not exceed
12.5 mg. At 50 mg/day, COREG reduced sitting trough (12-hour) blood pressure by about
9/5.5 mm Hg; at 25 mg/day the effect was about 7.5/3.5 mm Hg. Comparisons of trough to peak
blood pressure showed a trough to peak ratio for blood pressure response of about 65%. Heart
rate fell by about 7.5 beats/minute at 50 mg/day. In general, as is true for other β-blockers,
responses were smaller in black than non-black subjects. There were no age- or gender-related
differences in response.
26
The peak antihypertensive effect occurred 1 to 2 hours after a dose. The dose-related
blood pressure response was accompanied by a dose-related increase in adverse effects [see
Adverse Reactions (6)].
14.4 Hypertension With Type 2 Diabetes Mellitus
In a double-blind trial (GEMINI), COREG, added to an ACE inhibitor or angiotensin
receptor blocker, was evaluated in a population with mild-to-moderate hypertension and wellcontrolled type 2 diabetes mellitus. The mean HbA1c at baseline was 7.2%. COREG was titrated
to a mean dose of 17.5 mg twice daily and maintained for 5 months. COREG had no adverse
effect on glycemic control, based on HbA1c measurements (mean change from baseline of
0.02%, 95% CI: -0.06 to 0.10, P = NS) [see Warnings and Precautions (5.6)].
16
HOW SUPPLIED/STORAGE AND HANDLING
The white, oval, film-coated tablets are available in the following strengths: 3.125 mg –
engraved with 39 and SB, in bottles of 100; 6.25 mg – engraved with 4140 and SB, in bottles of
100; 12.5 mg – engraved with 4141 and SB, in bottles of 100; 25 mg – engraved with 4142 and
SB, in bottles of 100. The 6.25-mg, 12.5-mg, and 25-mg tablets are TILTAB tablets.
• 3.125 mg 100’s: NDC 0007-4139-20
• 6.25 mg 100’s: NDC 0007-4140-20
• 12.5 mg 100’s: NDC 0007-4141-20
• 25 mg 100’s: NDC 0007-4142-20
Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.
17
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information)
17.1 Patient Advice
Patients taking COREG should be advised of the following:
• Patients should take COREG with food.
• Patients should not interrupt or discontinue using COREG without a physician’s advice.
• Patients with heart failure should consult their physician if they experience signs or
symptoms of worsening heart failure such as weight gain or increasing shortness of breath.
• Patients may experience a drop in blood pressure when standing, resulting in dizziness and,
rarely, fainting. Patients should sit or lie down when these symptoms of lowered blood
pressure occur.
• If experiencing dizziness or fatigue, patients should avoid driving or hazardous tasks.
• Patients should consult a physician if they experience dizziness or faintness, in case the
dosage should be adjusted.
• Diabetic patients should report any changes in blood sugar levels to their physician.
• Contact lens wearers may experience decreased lacrimation.
COREG, COREG CR, and TILTAB are registered trademarks of GlaxoSmithKline.
TOPROL-XL is a registered trademark of the AstraZeneca group of companies.
27
Manufactured for
GlaxoSmithKline
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline. All rights reserved.
CRG:23PI
28
PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT
------------------------------------------------------------------------------------------------------------PATIENT INFORMATION
COREG® (Co-REG)
Carvedilol Tablets
Read the Patient Information that comes with COREG before you start taking it and
each time you get a refill. There may be new information. This information does not
take the place of talking with your doctor about your medical condition or your
treatment. If you have any questions about COREG, ask your doctor or pharmacist.
What is COREG?
COREG is a prescription medicine that belongs to a group of medicines called “betablockers”. COREG is used, often with other medicines, for the following conditions:
• to treat patients with certain types of heart failure
• to treat patients who had a heart attack that worsened how well the heart
pumps
• to treat patients with high blood pressure (hypertension)
COREG is not approved for use in children under 18 years of age.
Who should not take COREG?
Do not take COREG if you:
• have severe heart failure and are hospitalized in the intensive care unit or
require certain intravenous medications that help support circulation (inotropic
medications).
• are prone to asthma or other breathing problems.
• have a slow heartbeat or a heart that skips a beat (irregular heartbeat).
• have liver problems.
• are allergic to any of the ingredients in COREG. The active ingredient is
carvedilol. See the end of this leaflet for a list of all the ingredients in COREG.
What should I tell my doctor before taking COREG?
Tell your doctor about all of your medical conditions, including if you:
• have asthma or other lung problems (such as bronchitis or emphysema).
• have problems with blood flow in your feet and legs (peripheral vascular
disease). COREG can make some of your symptoms worse.
• have diabetes.
• have thyroid problems.
29
•
•
•
•
•
•
•
have a condition called pheochromocytoma.
have had severe allergic reactions.
are pregnant or trying to become pregnant. It is not known if COREG is safe for
your unborn baby. You and your doctor should talk about the best way to
control your high blood pressure during pregnancy.
are breastfeeding. It is not known if COREG passes into your breast milk. You
should not breastfeed while using COREG.
are scheduled for surgery and will be given anesthetic agents.
are scheduled for cataract surgery and have taken or are currently taking
COREG.
are taking prescription or non-prescription medicines, vitamins, and herbal
supplements. COREG and certain other medicines can affect each other and
cause serious side effects. COREG may affect the way other medicines work.
Also, other medicines may affect how well COREG works.
Keep a list of all the medicines you take. Show this list to your doctor and
pharmacist before you start a new medicine.
How should I take COREG?
It is important for you to take your medicine every day as directed by your
doctor. If you stop taking COREG suddenly, you could have chest pain
and/or a heart attack. If your doctor decides that you should stop taking
COREG, your doctor may slowly lower your dose over a period of time
before stopping it completely.
• Take COREG exactly as prescribed. Your doctor will tell you how many tablets to
take and how often. In order to minimize possible side effects, your doctor
might begin with a low dose and then slowly increase the dose.
• Do not stop taking COREG and do not change the amount of COREG you
take without talking to your doctor.
• Tell your doctor if you gain weight or have trouble breathing while taking
COREG.
• Take COREG with food.
• If you miss a dose of COREG, take your dose as soon as you remember, unless
it is time to take your next dose. Take your next dose at the usual time. Do not
take 2 doses at the same time.
• If you take too much COREG, call your doctor or poison control center right
away.
30
What should I avoid while taking COREG?
• COREG can cause you to feel dizzy, tired, or faint. Do not drive a car, use
machinery, or do anything that needs you to be alert if you have these
symptoms.
What are possible side effects of COREG?
• Low blood pressure (which may cause dizziness or fainting when you
stand up). If these happen, sit or lie down right away and tell your doctor.
• Tiredness. If you feel tired or dizzy you should not drive, use machinery, or do
anything that needs you to be alert.
• Slow heartbeat.
• Changes in your blood sugar. If you have diabetes, tell your doctor if
you have any changes in your blood sugar levels.
• COREG may hide some of the symptoms of low blood sugar, especially a fast
heartbeat.
• COREG may mask the symptoms of hyperthyroidism (overactive thyroid).
• Worsening of severe allergic reactions.
• Rare but serious allergic reactions (including hives or swelling of the face,
lips, tongue, and/or throat that may cause difficulty in breathing or swallowing)
have happened in patients who were on COREG. These reactions can be lifethreatening.
Other side effects of COREG include shortness of breath, weight gain, diarrhea, and
fewer tears or dry eyes that become bothersome if you wear contact lenses.
Call your doctor if you have any side effects that bother you or don’t go away.
Call your doctor for medical advice about side effects. You may report side effects
to FDA at 1-800-FDA-1088.
How should I store COREG?
• Store COREG at less than 86°F (30°C). Keep the tablets dry.
• Safely, throw away COREG that is out of date or no longer needed.
• Keep COREG and all medicines out of the reach of children.
General Information about COREG
Medicines are sometimes prescribed for conditions other than those described in
patient information leaflets. Do not use COREG for a condition for which it was not
prescribed. Do not give COREG to other people, even if they have the same
symptoms you have. It may harm them.
31
This leaflet summarizes the most important information about COREG. If you would
like more information, talk with your doctor. You can ask your doctor or pharmacist
for information about COREG that is written for healthcare professionals. You can
also find out more about COREG by visiting the website www.COREG.com or calling
1-888-825-5249. This call is free.
What are the ingredients in COREG?
Active Ingredient: carvedilol.
Inactive Ingredients: colloidal silicon dioxide, crospovidone, hypromellose, lactose,
magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sucrose, and
titanium dioxide.
Carvedilol tablets come in the following strengths: 3.125 mg, 6.25 mg, 12.5 mg,
25 mg.
What is high blood pressure (hypertension)?
Blood pressure is the force of blood in your blood vessels when your heart beats
and when your heart rests. You have high blood pressure when the force is too
much. High blood pressure makes the heart work harder to pump blood through the
body and causes damage to blood vessels. COREG can help your blood vessels
relax so your blood pressure is lower. Medicines that lower blood pressure may
lower your chance of having a stroke or heart attack.
COREG is a registered trademark of GlaxoSmithKline.
Manufactured for
GlaxoSmithKline
Research Triangle Park, NC 27709
©2013, GlaxoSmithKline. All rights reserved.
August 2013
CRG:5PIL
32